Ledipasvir + sofosbuvir (Harvoni). A therapeutic advance in genotype 1 hepatitis C virus infection, despite uncertainties.

Treatment for chronic hepatitis C depends on the hepatitis C virus (HCV) genotype and the patient's clinical characteristics. A fixed-dose combination of ledipasvir + sofosbuvir has been authorised in the European Union for adults with HCV genotype 1 (HCV-1), HCV-3 or HCV-4 infection. Ledipasvir targets the HCV protein NS5A, while sofosbuvir inhibits the HCV RNA polymerase NS5B. The ledipasvir+ sofosbuvircombination has not been compared directly with other antiviral drugs. No information is available on its ability to prevent hepatic complications, even in patients with cirrhosis. In four trials including over 1800 treatment-naive patients infected with HCV-1, a 12-week course of ledipasvir + sofosbuviryielded a sustained virological response in nearly every case. This is better than that reported with peginterferon alfa-based protocols. In four trials including more than 900 HCV-1-infected patients in whom treatments including peginterferon alfa had failed, a 24-week course of ledipasvir+ sofosbuvir yielded a sustained virological response in nearly every case, which is far better than reported with peginterferon alfa + ribavirin + protease inhibitor combinations, based on indirect comparison. In these trials, a 24-week course of the ledipasvir + sofosbuvir combination was effective in almost all patients with compensated cirrhosis. The same treatment also showed major efficacy in a non-comparative trial in 337 HCV-1-infected patients with decompensated cirrhosis or who had undergone liver transplantation. In mid-2015, very few data are available on the ledipasvir + sofosbuvir combination in HCV-1-infected patients in whom sofosbuvir combination therapy has failed, or in patients with HCV-3 or HCV-4 infection. Comparative data on the adverse effects of the ledipasvir + sofosbuvir combination are mainly based on a double-blind, placebo-controlled trial in 155 patients. Overall, serious adverse effects were infrequent in this and other trials. The main adverse effects appear to be headache, fatigue, sleep disorders, irritability and lipase elevations. Hypertension, muscle disorders and dyspnoea are other plausible adverse effects. Bradycardia and cardiac conduction disorders have been reported with concomitant use of sofosbuvir and amiodarone, an antiarrhythmic drug. In practice, in mid-2015, when drug therapy is warranted for chronic hepatitis C due to HCV genotype 1, the ledipasvir + sofosbuvir combination is a first-choice treatment because of its virological efficacy, despite its poorly documented adverse effects. These important outstanding questions call for rigorous pharmacovigilance on the part of all healthcare professionals. It is too early to recommend the ledipasvir + sofosbuvir combination for patients infected with other HCV genotypes. The exorbitant price imposed by Gilead endangers public healthcare systems and undermines access to high-quality care.